Researchers at Tel Aviv University say they have found an innovative gene therapy method to treat impairments in hearing and balance caused by inner ear dysfunction, providing hope for a cure to inherited deafness.
“This treatment holds promise for treating a wide range of mutations that cause hearing loss,� said lead scientist Prof. Karen Avraham, Dean of Tel Aviv’s Gray Faculty of Medical & Health Sciences, speaking to The Times of Israel in a teleconference call recently alongside Roni Hahn, a PhD student.
The work was conducted in collaboration with Prof. Jeffrey Holt and Dr. Gwenaëlle Géléoc, both of Boston Children’s Hospital and Harvard Medical School, with support from the US-Israel Binational Science Foundation, the US National Institutes of Health, and the Israel Science Foundation Breakthrough Research Program.
The gene therapy method, tried for the first time to treat inherited hearing loss, was featured last month on the cover of peer-reviewed EMBO Molecular Medicine.
“While there has been gene therapy for other diseases in the past decade, somehow there was this kind of ceiling with deafness because of the complexity of the inner ear and the difficulty in reaching it,� said Avraham. “The breakthroughs in the field in recent years are a dream come true.�
Approximately one in every 1,000 children is born deaf or hard of hearing, according to the National Institutes of Health.
Hearing loss is the most common sensory impairment worldwide, said Avraham, and over half of congenital cases are caused by genetic factors.
The inner ear consists of two highly coordinated systems, Avraham explained. There is the auditory system, which detects, processes, and transmits sound signals to the brain. And there is the vestibular system, which enables spatial orientation and balance.
“A wide range of genetic variants in DNA can affect the function of these systems, leading to hearing loss and balance problems,� said Avraham, who has worked in the field for 30 years, pioneering the discovery of genes that cause deafness, and has led more than 100 studies on hearing loss.
According to Hahn, gene therapy has emerged as a powerful therapeutic approach in recent years and is now being applied to a range of genetic disorders, including spinal muscular atrophy (SMA), which affects muscles, and Leber congenital amaurosis (LCA), which causes blindness. It is also used in some cancer immunotherapy approaches, such as CAR T-cell therapy, a cancer treatment that uses a patient’s own immune cells to fight tumors.
One way gene therapy works is by using engineered viruses as delivery tools. Scientists remove the virus’s own DNA and replace it with a functional copy of the gene they want to fix. Because viruses are naturally good at entering cells, they can carry the corrected gene into the patient’s cells, helping them work properly again.
For hearing loss, most preclinical studies utilize AAVs (adeno-associated viruses) as delivery tools.
An AAV is a tiny, non-pathogenic virus that doesn’t cause disease in humans, the researchers said. It acts like a delivery service, carrying a healthy new gene into the patient’s cells, fixing or improving the disease.
For hearing loss research, AAVs are especially useful because they can get into the hair cells of the inner ear, which are otherwise very hard to reach.
When the virus delivers the gene into a cell, the DNA arrives as a single strand. The cell then has to fill in the missing strand before it can use the gene to make a healthy protein.
That extra step takes time and sometimes lowers efficiency.
Instead, the research team used what’s known as a Self-complementary AAV (scAAV), an optimized version, in which the virus already carries two matching strands of DNA.
The researchers found that the scAAV was faster and more efficient.
Avraham said that speed is an advantage because “there isn’t a lot of time before the damage occurs� to hearing.
“Once the hair cells of the ear are damaged, we cannot reverse it back,” Hahn added.
The experiments were conducted in mouse models, which are widely used in hearing research.
“For most of the genes that have been found to cause deafness in humans, there’s a counterpart in mice,� Avraham said. “The human inner ear is obviously a little bigger than the ears of these furry little things, but the structure and the function of the inner ear are remarkably similar, so it’s really an excellent model.�
In this study, the researchers investigated a mutation in the CLIC5 gene, which is essential for maintaining the stability and function of hair cells in the auditory and vestibular systems. Deficiency of this gene causes progressive degeneration of hair cells, initially leading to hearing loss and later resulting in balance problems. Avraham said that many people with a hearing loss cannot walk in a straight line in the darkness.
Hahn added that the knowledge gained in gene therapy in one field can be applied to others.
“What we’re doing for hearing loss is similar to what has been done before for the eye and for other diseases,â€� she said. “A tool used for gene therapy in one system can be modified and used in others, accelerating the development of treatments across multiple genetic disorders.â€�
Avraham’s team of researchers has provided genetic diagnosis for the hearing loss of approximately 60% of Israelis among diverse populations, laying the groundwork for candidates for gene therapy.
“We care very much about finding solutions in our own region,â€� Avraham said. “One of the things that we’re doing now, in collaboration with medical centers in the greater Tel Aviv area, is screening all children who are born deaf.”
“We want to map out what’s happening in Israel. If clinical trials for new drugs come to Israel in the near future,” she said, “then hospitals will be able to treat children as early as possible.”